Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations

被引：45

作者：

Aldrian, Denise ^{[1
]}

Vogel, Georg F. ^{[1
,2
]}

Frey, Teresa K. ^{[1
]}

Ayyildiz Civan, Hasret ^{[3
]}

Aksu, Aysel Unlusoy ^{[4
]}

Avitzur, Yaron ^{[5
]}

Ramos Boluda, Esther ^{[6
]}

Cakir, Murat ^{[7
,8
]}

Demir, Arzu Meltem ^{[9
]}

Deppisch, Caroline ^{[10
]}

Duba, Hans-Christoph ^{[11
]}

Dueker, Gesche ^{[12
]}

Gerner, Patrick ^{[13
]}

Hertecant, Jozef ^{[14
]}

Hornova, Jarmila ^{[15
]}

Kathemann, Simone ^{[16
]}

Koeglmeier, Jutta ^{[17
]}

Koutroumpa, Arsinoi ^{[18
]}

Lanzersdorfer, Roland ^{[19
]}

Lev-Tzion, Raffi ^{[20
]}

Lima, Rosa ^{[21
]}

Mansour, Sahar ^{[22
]}

Meissl, Manfred ^{[23
]}

Melek, Jan ^{[24
]}

Miqdady, Mohamad ^{[25
]}

Montoya, Jorge Hernan ^{[26
]}

Posovszky, Carsten ^{[27
]}

Rachman, Yelena ^{[20
]}

Siahanidou, Tania ^{[28
]}

Tabbers, Merit ^{[29
]}

Uhlig, Holm H. ^{[30
,31
]}

Unal, Sevim ^{[32
]}

Wirth, Stefan ^{[33
]}

Ruemmele, Frank M. ^{[34
,35
]}

Hess, Michael W. ^{[36
]}

Huber, Lukas A. ^{[37
,38
]}

Mueller, Thomas ^{[1
]}

Sturm, Ekkehard ^{[39
]}

Janecke, Andreas R. ^{[1
,40
]}

机构：

[1] Med Univ Innsbruck, Dept Pediat 1, A-6020 Innsbruck, Austria

[2] Med Univ Innsbruck, Div Cell Biol, Bioctr, A-6020 Innsbruck, Austria

[3] Hlth Sci Univ, Sadi Konuk Educ & Res Hosp, Dept Pediat Gastroenterol Hepatol & Nutr, TR-34147 Istanbul, Turkey

[4] Univ Hlth Sci, Dr Sami Ulus Matern & Child Hlth & Dis Training &, TR-06120 Ankara, Turkey

[5] Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON M5G 0A4, Canada

[6] Univ Hosp La Paz, Intestinal Rehabil Unit, Pediat Gastroenterol & Nutr Unit, Madrid 28046, Spain

[7] Karadeniz Tech Univ, Fac Med, Dept Pediat Gastroenterol Hepatol, TR-61080 Trabzon, Turkey

[8] Karadeniz Tech Univ, Fac Med, Dept Nutr, TR-61080 Trabzon, Turkey

[9] Training & Res Hosp, Ankara Child Hlth & Dis, Pediat Gastroenterol, TR-06130 Ankara, Turkey

[10] Univ Klin Kinder & Jugendmed Tubingen, Padiatr Gastroenterol & Hepatol, Hoppe Seyler Str 1, D-72076 Tubingen, Germany

[11] Johannes Kepler Univ Linz, Kepler Univ Hosp, Sch Med, Dept Med Genet, A-4020 Linz, Austria

[12] Univ Childrens Hosp Bonn, Dept Pediat Gastroenterol & Hepatol, D-53127 Bonn, Germany

[13] Univ Freiburg, Dept Pediat & Adolescent Med, Med Ctr, Fac Med, D-79106 Freiburg, Germany

[14] Tawam Hosp, Genet Metabol Serv, Al Ain 15258, U Arab Emirates

[15] Comenius Univ, Natl Inst Children Dis, Dept Pediat, Fac Med, Bratislava 81499, Slovakia

[16] Univ Duisburg Essen, Univ Childrens Hosp Essen, Dept Pediat Nephrol Gastroenterol Endocrinol & Tr, Clin Pediat 2, D-45147 Essen, Germany

[17] Great Ormond St Hosp Sick Children NHS Fdn Trust, Dept Paediat Gastroenterol, Unit Nutr & Intestinal Failure Rehabil, Great Ormond St, London WC1N 3JH, England

[18] Aghia Sofia Childrens Hosp, Neonatal Intens Care Unit B, Athens 11527, Greece

[19] Johannes Kepler Univ Linz, Dept Paediat & Adolescent Med, A-4020 Linz, Austria

[20] Shaare Zedek Med Ctr, Pediat Gastroenterol, IL-9103102 Jerusalem, Israel

[21] Ctr Hosp Porto, Unidade Gastrenterol Pediat, P-4099001 Porto, Portugal

[22] St Georges Univ NHS Fdn Trust, SW Thames Reg Genet Serv, London SW17 0QT, England

[23] Johannes Kepler Univ Linz, Dept Neonatol, A-4020 Linz, Austria

[24] Charles Univ Prague, Fac Med Hradec Kralove, Dept Pediat, Pediat Gastroenterol, Prague 11000, Czech Republic

[25] Khalife Univ, Dept Pediat, Coll Med & Hlth Sci, Sheikh Khalifa Med City, Abu Dhabi 127788, U Arab Emirates

[26] Hosp Univ San Vicente Paul, Medellin 50022, Antioquia, Colombia

[27] Univ Med Ctr Ulm, Dept Pediat & Adolescent Med, Eythstr 24, D-89075 Ulm, Germany

[28] Athens Univ, Dept Pediat 1, Med Sch, Athens 11527, Greece

[29] Emma Childrens Hosp AMC, NL-1105 Amsterdam, Netherlands

[30] Univ Oxford, Translat Gastroenterol Unit, Oxford OX3 9DU, England

[31] Univ Oxford, Dept Pediat, Oxford OX3 9DU, England

[32] Training & Res Hosp, Ankara Child Hlth & Dis, Neonatol, TR-06120 Ankara, Turkey

[33] Witten Herdecke Univ, Dept Paediat, Helios Med Ctr Wuppertal, D-58455 Witten, Germany

[34] Hop Univ Necker Enfants, AP HP, Malades Serv Gastroenterol Hepatol & Nutr Pediat, 149 Rue Sevres, F-75015 Paris, France

[35] Univ Paris, Paediat Med Fac, F-75005 Paris, France

[36] Med Univ Innsbruck, Inst Histol & Embryol, A-6020 Innsbruck, Austria

[37] Med Univ Innsbruck, Div Cell Biol, A-6020 Innsbruck, Austria

[38] ADSI, Austrian Drug Screening Inst, A-6020 Innsbruck, Austria

[39] Childrens Hosp Tubingen, D-72076 Tubingen, Germany

[40] Med Univ Innsbruck, Div Human Genet, A-6020 Innsbruck, Austria

来源：

JOURNAL OF CLINICAL MEDICINE | 2021年 / 10卷 / 03期

关键词：

congenital diarrheal diseases; enteropathy; microvillus inclusion disease; MYO5B; myosin Vb; progressive familial intrahepatic cholestasis; PFIC; genotype– phenotype correlation; lack of protein; tail domain; MICROVILLUS INCLUSION DISEASE; INTESTINAL FAILURE; EPITHELIAL-CELLS; MYOSIN VB; TRAFFICKING; CHILDREN; REVEALS; MODEL; MICE;

D O I：

10.3390/jcm10030481

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.

引用

页码：1 / 15

页数：15

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